Targeting the adipose tissue: heart crosstalk in pressure overload-induced heart failure

This editorial refers to ‘Resistin deletion protects against heart failure injury by targeting DNA damage response’ by Zhao et al., https://doi.org/10.1093/cvr/cvab234. Following an excessive haemodynamic or metabolic stress, the heart initiates a compensatory adaptive response leading to the development of left ventricular hypertrophy.1 The persistence of this stress may lead to heart failure, a leading cause of mortality worldwide. Accumulating evidence from preclinical and clinical studies suggests that maladaptation of adipose tissue to stress conditions contributes to cardiac dysfunction and cardiovascular mortality. However, the underlying mechanisms are not completely understood. Adipose tissue is a metabolically active endocrine organ that communicates with all organs by producing chemical messengers such as adipokines and cytokines, which elicit a variety of local and systemic responses. The adipose tissue considerably impacts cardiovascular physiology by exerting both protective and deleterious effects on the cardiovascular function depending on the secreted product.2 Among these messengers, resistin, an adipose tissue-derived hormone, is primarily secreted from mature white adipocytes in rodents,2 while it is mainly released by adipose tissue-infiltrated monocytes and macrophages in humans.3 Resistin is also expressed at low levels in the heart, but its expression levels are increased considerably under stress conditions such as in diabetes, pressure overload, or after myocardial injury.2 Several epidemiologic studies have shown that resistin is a poor prognostic factor in heart failure patients. Serum levels of resistin were reported to be increased in patients with heart failure and they were positively associated with the severity of heart failure according to the NYHA classification.4 Importantly, circulating resistin levels were independently associated with indexes of left ventricular structural changes including left ventricular mass hypertrophy in a large community-based cohort.5 The mechanisms underlying the association of circulating resistin levels with heart failure progression and prognosis have been the topic of intense research. In this regard, resistin was first discovered as a peptide playing a significant role in the development of insulin resistance.3 Furthermore, resistin is induced in response to pro-inflammatory stimuli and can contribute to the immune response through the up-regulation of pro-inflammatory cytokines.6 While both insulin resistance and inflammation are major contributing factors to the development or progression of heart failure, higher circulating resistin levels were strongly associated with subsequent development of cardiac dysfunction even after accounting for obesity, insulin resistance, inflammation, and incident coronary heart disease over a 6-year follow-up time period in the Framingham Offspring Study.7 These findings raise the question of a direct relationship between resistin and heart failure via mechanisms independent of insulin resistance and inflammation. The present manuscript by Zhao et al.8 published in this issue of Cardiovascular Research revealed that deletion of resistin in adipose tissue partially prevents pressure overload-induced cardiac hypertrophy and heart failure (Figure 1). Using adipose tissue-restricted resistin knockout (RKO) mice and by challenging them with a transverse aortic constriction, a well-established experimental pressure overload-induced cardiac hypertrophy-related heart failure model, the authors report that the deletion of resistin in adipose tissue strikingly improved the ejection fraction by 28%, increased cardiac contractility, decreased myocardial fibrosis, and drastically improved survival by 70% compared to wild-type mice. At the same time, cardiac-specific overexpression of resistin in RKO mice showed the exact opposite effects characterized by a reduction in cardiac contractility, increased fibrosis, and premature death.8 These findings support and expand a previous report from the same research group showing that resistin overexpression in rats increased oxidative stress and inflammation leading to cardiac remodelling and hypertrophy.9 Adipose tissue-heart crosstalk in pressure overload-induced heart failure. Adipose tissue-restricted genetic deletion of resistin in a mouse model of pressure overload-induced heart failure reduced cardiac hypertrophy and subsequent heart failure, while drastically improved the survival of the mice. Targeting the downstream signaling of resistin in heart protects the heart against cardiac fibrosis and DNA damage-induced pathological cardiac remodelling. Figure created with Servier Medical Art (https://smart.servier.com/). With the help of RNA-sequencing of the mouse heart after transverse aortic constriction, the authors identified a 50% increase in the growth arrest DNA damage-inducible protein 45 alpha (Gadd45α) in the RKO mice compared to the wild-type mice. Both DNA damage and deficient DNA damage response activation have been observed in the failing hearts contributing to cardiac dysfunction.10 Given that Gadd45α is essential for the maintenance of genomic stability and DNA repair process, Zhao et al.8 showed that both pressure overload-induced heart failure and resistin overexpression lead to increased DNA damage. In contrast, the deletion of resistin in adipose tissue prevented DNA damage and cardiac dysfunction. Importantly, Zhao et al. identified Gadd45α as a bona fide target of miR-148b-3p. Strikingly, resistin inhibition decreased, while resistin overexpression increased, miR-148b-3p expression in the RKO-TAC hearts.8 Therapeutic inhibition of miR-148b-3p with locked nucleic acid-modified antisense oligonucleotides (LNA) in the failing heart drastically protects against adverse cardiac remodelling and cardiac fibrosis and restores the DNA damage response. Finally, the authors found that human resistin and miR-148b-3p are up-regulated, while Gadd45α is down-regulated, in human cardiac failing tissues, paralleling the mouse data.8 The present study by Zhao et al.8 clearly suggests that adipose tissue-derived resistin is not only a heart failure biomarker, but it significantly contributes to cardiac remodelling and heart failure under pressure-overload conditions. These findings spark new interest in the potential therapeutic impact of modulation of adipose tissue-derived hormones including resistin in pressure overload-induced heart failure. Considering that depending on its location and metabolic state the adipose tissue shows striking biological variability, it is important to determine the cause behind the increased resistin levels in heart failure. While the receptor of resistin has not been identified yet, identifying resistin-specific signalling mechanisms is an essential step towards the development of novel therapeutics targeting the adipose tissue—heart crosstalk in heart failure. Preclinical studies including large animal disease models and early clinical trials are needed to evaluate the specificity, efficacy, and safety of LNA-miR-148b-3p inhibitors as a potential RNA therapeutic for the treatment of pressure overload-induced cardiac hypertropy and heart failure. Given that we are living the dawn of RNA therapeutics in cardiovascular disease, further studies are called to validate the therapeutic potential of modulating resistin levels in patients with heart failure. K.S. is supported by grants from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (MODVASC, grant agreement No. 759248) and the German Research Foundation DFG (SFB834 B12, project number 75732319). Conflict of interest: none declared.